Novel model of secreted human tau protein reveals the impact of the abnormal N-glycosylation of tau on its aggregation propensity.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and has no disease-modifying treatment yet. The hallmarks of AD are two amyloidogenic proteins: tau and amyloid β (Aβ). Tau undergoes several posttranslational modifications， including N-glycosylation. Tau was reported to be N-glycosylated in AD brains， but not in healthy counterparts， which may affect AD etiology. Here， we aimed to examine the effect of N-glycosylation on aggregation propensity of tau. To that end， a novel SH-SY5Y cell-based model was generated in which recombinant human tau (htau) is forced to be secreted from the cells. Secreted htau was found to localize in the secretory pathway compartments and to undergo N-glycosylation. Following N-glycan cleavage of the secreted htau， various biophysical results collectively indicated that the untreated N-glycosylated secreted htau is markedly less aggregative， contains thinner and shorter fibrils， as compared to treated de-glycosylated secreted htau. This finding shows that N-glycans attached to htau may affect its aggregation. This could help to better understand the effect of N-glycosylated htau on AD progression.